Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor

The design, synthesis and validation of a family of small molecule “Dual-Action Virucidal EntryInhibitors” (DAVEIs) has been achieved that result in irreversible lytic inactivation of HIV-1 virions. These constructs contained two functional components that endow the capacity to bindsimultaneously to both the gp120 and gp41 subunits of the HIV-1 Envelope glycoprotein (Env). One component is derived from BNM-III-170, a small molecule CD4 mimic warhead that binds togp120. The second component, a Trp3 peptide, is a 9-amino acid segment based on the gp41 Membrane Proximal External Region (MPER) that has been proposed to bind to the gp41 MPERdomain of the Env. The resulting smDAVEIs both inhibit infection with low micromolar potency and induce lysis of the HIV-1 virion. The lytic activity was selective for functional HIV-1 virions. Crucially, virolysis was found to be dependent on covalent tethering of the BNM-III-170 and Trp3 domains with various spacers, as coadministration of the un-crosslinked components proved not to be lytic. Computational modeling supports a mechanism in which DAVEIs bind to open-state Env trimers and induce relative motion of gp120 subunits that further opens the trimers. Overall, this work represents a promising new step toward the use of small-molecule DAVEIs for eradication of HIV.

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Field-Based Affinity Optimization of a Novel Azabicyclohexane Scaffold HIV-1 Entry Inhibitor

Molecules ◽

10.3390/molecules24081581 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1581 ◽

Cited By ~ 6

Author(s):

Megan E. Meuser ◽

Adel A. Rashad ◽

Gabriel Ozorowski ◽

Alexej Dick ◽

Andrew B. Ward ◽

...

Keyword(s):

Kinetic Parameter ◽

Small Molecule ◽

Conformational Equilibrium ◽

Therapeutic Modality ◽

Entry Inhibitor ◽

Entry Inhibitors ◽

Antiviral Compounds ◽

Novel Strategy ◽

Positive Effect ◽

Hiv 1

Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.

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Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid

Journal of Virology ◽

10.1128/jvi.05006-11 ◽

2012 ◽

Vol 86 (16) ◽

pp. 8472-8481 ◽

Cited By ~ 44

Author(s):

Sandhya Kortagere ◽

Navid Madani ◽

Marie K. Mankowski ◽

Arne Schön ◽

Isaac Zentner ◽

...

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Mononuclear Cells ◽

Early Stage ◽

Titration Calorimetry ◽

Compound I ◽

Peripheral Blood Mononuclear ◽

Anti Hiv ◽

Hiv 1 ◽

Ca Protein

The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication and has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential to interact with the N-terminal domain (NTD) of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4′-[dibenzo[b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections but failed to inhibit viral replication in peripheral blood mononuclear cells (PBMCs), was identified. Three analogues of CK026 with reduced size and better drug-like properties were synthesized and assessed. Compound I-XW-053 (4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid) retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of nonretroviruses. Direct interaction of I-XW-053 was quantified with wild-type and mutant CA protein using surface plasmon resonance and isothermal titration calorimetry. Mutation of Ile37 and Arg173, which are required for interaction with compound I-XW-053, crippled the virus at an early, preintegration step. Using quantitative PCR, we demonstrated that treatment with I-XW-053 inhibited HIV-1 reverse transcription in multiple cell types, indirectly pointing to dysfunction in the uncoating process. In summary, we have identified a CA-specific compound that targets and inhibits a novel region in the NTD-NTD interface, affects uncoating, and possesses broad-spectrum anti-HIV-1 activity.

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A targeted covalent small molecule inhibitor of HIV-1 fusion

Chemical Communications ◽

10.1039/d1cc01013a ◽

2021 ◽

Author(s):

Guangyan Zhou ◽

Li He ◽

Kathy H. Li ◽

Cássio C. S. Pedroso ◽

Miriam Gochin

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Covalent Bond ◽

Small Molecule Inhibitor ◽

Hydrophobic Pocket ◽

Molecule Inhibitor ◽

Hiv 1

Formation of a covalent bond with a conserved lysine in the hydrophobic pocket of HIV-1 gp41 boosted antiviral activity of a small molecule inhibitor.

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Structure of BMS-806, a Small-molecule HIV-1 Entry Inhibitor, Bound to BG505 SOSIP.664 HIV-1 Env Trimer

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.5307c.abstract ◽

2014 ◽

Vol 30 (S1) ◽

pp. A151-A151 ◽

Cited By ~ 2

Author(s):

Marie Pancera ◽

Aliaksandr Druz ◽

Tongqing Zhou ◽

Sijy O'Dell ◽

Mark Louder ◽

...

Keyword(s):

Small Molecule ◽

Entry Inhibitor ◽

Hiv 1

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Irreversible HIV-1 Inactivation Employing a Small Molecule Dual-Action Virolytic Entry Inhibitor Strategy

10.26434/chemrxiv.8966363.v1 ◽

2019 ◽

Author(s):

Althea Gaffney ◽

Aakansha Nangarlia ◽

Steven Gossert ◽

Adel A. Rashad ◽

Alamgir Hossain ◽

...

Keyword(s):

Amino Acid ◽

Small Molecule ◽

Envelope Glycoprotein ◽

Entry Inhibitor ◽

External Region ◽

Design Synthesis ◽

Dual Action ◽

Functional Components ◽

Amino Acid Segment ◽

Hiv 1

The design, synthesis and validation of a family of small molecule “Dual-Action Virucidal EntryInhibitors” (DAVEIs) has been achieved that result in irreversible lytic inactivation of HIV-1 virions. These constructs contained two functional components that endow the capacity to bindsimultaneously to both the gp120 and gp41 subunits of the HIV-1 Envelope glycoprotein (Env). One component is derived from BNM-III-170, a small molecule CD4 mimic warhead that binds togp120. The second component, a Trp3 peptide, is a 9-amino acid segment based on the gp41 Membrane Proximal External Region (MPER) that has been proposed to bind to the gp41 MPERdomain of the Env. The resulting smDAVEIs both inhibit infection with low micromolar potency and induce lysis of the HIV-1 virion. The lytic activity was selective for functional HIV-1 virions. Crucially, virolysis was found to be dependent on covalent tethering of the BNM-III-170 and Trp3 domains with various spacers, as coadministration of the un-crosslinked components proved not to be lytic. Computational modeling supports a mechanism in which DAVEIs bind to open-state Env trimers and induce relative motion of gp120 subunits that further opens the trimers. Overall, this work represents a promising new step toward the use of small-molecule DAVEIs for eradication of HIV.

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Antiviral Activity, Pharmacokinetics, and Safety of BMS-488043, a Novel Oral Small-Molecule HIV-1 Attachment Inhibitor, in HIV-1-Infected Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00759-10 ◽

2010 ◽

Vol 55 (2) ◽

pp. 722-728 ◽

Cited By ~ 37

Author(s):

George J. Hanna ◽

Jacob Lalezari ◽

James A. Hellinger ◽

David A. Wohl ◽

Richard Nettles ◽

...

Keyword(s):

Antiviral Activity ◽

Small Molecule ◽

Drug Exposure ◽

Antiviral Response ◽

Treatment Groups ◽

Viral Susceptibility ◽

Lower Baseline ◽

Molecule Inhibitor ◽

Group A ◽

Hiv 1

ABSTRACTBMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4+lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log10copies/ml, respectively, compared with 0.02 log10copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC50) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration (Ctrough), adjusted by the baseline EC50(Ctrough/EC50), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted.

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Direct Inactivation of Human Immunodeficiency Virus Type 1 by a Novel Small-Molecule Entry Inhibitor, DCM205

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01001-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1780-1786 ◽

Cited By ~ 6

Author(s):

Yen T. Duong ◽

D. Christopher Meadows ◽

Indresh K. Srivastava ◽

Jacquelyn Gervay-Hague ◽

Thomas W. North

Keyword(s):

Human Immunodeficiency Virus ◽

Small Molecule ◽

Sexual Transmission ◽

Entry Inhibitor ◽

Molecule Inhibitor ◽

Cellular Target ◽

Immunodeficiency Virus ◽

Hiv Entry ◽

Hiv 1

ABSTRACT With more than 40 million people living with human immunodeficiency virus (HIV), there is an urgent need to develop drugs that can be used in the form of a topical microbicide to prevent infection through sexual transmission. DCM205 is a recently discovered small-molecule inhibitor of HIV type 1 (HIV-1) that is able to directly inactivate HIV-1 in the absence of a cellular target. DCM205 is active against CXCR4-, CCR5-, and dual-tropic laboratory-adapted and primary strains of HIV-1. DCM205 binds to the HIV-1 envelope glycoprotein, and competition studies map the DCM205 binding at or near the V3 loop of gp120. Binding to this site interferes with the soluble CD4 interaction. With its ability to disable the virus particle, DCM205 represents a promising new class of HIV entry inhibitor that can be used as a strategy in the prevention of HIV-1/AIDS.

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